This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. The long-range goal of this research project is to understand the molecular regulation of vertebrate limb regeneration, and apply this information toward designing therapies that restore regenerative responses in the limbs of higher vertebrates (including humans) that have lost this ability. The ability to regrow functional appendages lost to trauma or disease is a significant biomedical problem, potentially impacting 1.9 million afflicted persons in the US alone. While the tissue interactions regulating limb regeneration have been well-characterized over decades of research on urodele salamanders, essentially the only model organisms employed to date, the molecular signals initiating and maintaining regenerative responses are only beginning to be elucidated. Progress has been constrained by two critical limitations: first, the lack of diversity in experimental models has not exploited the power of comparative analyses;second, reliance on limb-patterning candidate gene approaches have not fundamentally informed our understanding of regeneration-specific molecular and physiological signals initiating limb regrowth. To address these shortcomings, this project will implement novel comparative analyses, including systems-level functional genomic approaches, to understand the cellular and molecular basis of regeneration in evolutionarily disparate vertebrate organisms such as sharks, skates, and primitive freshwater fish species. Adopting a novel comparative approach should reveal unexpected commonalities and differences in the basic mechanisms of vertebrate limb/fin regeneration, and yield insight into why amniotes such as humans have lost this ability, which is a fundamental step in developing human clinical therapies for traumatic limb loss.